The world population has a tendency towards aging. In view of the increasing population suffering from chronic diseases caused by aging, pharmaceutical companies around the world have been developing new drugs for treating chronic diseases to improve the quality of life for those suffering from chronic diseases. However, many drugs which are being, or soon to be, marketed are usually accompanied by an acute liver side effect emerging in some patients (patients with minor symptoms would stop taking the drugs, and those with severe symptoms would undergo a liver transplant, and at a critical stage might die) and were banned. Since these spontaneous liver side effects are related to the special constitution of patients or the inter-reaction between drugs, and the occurrence rate is extremely low (generally lower than 0.1%), it is unpredictable to doctors and patients, and even to pharmaceutical companies during the clinical trial period of the drug. Recalling a drug which is therapeutically beneficial to the majority of patients but posing severe safety concern to very few patients, is one of the dilemma the medical industry facing today.
The medical industry is at a loss on the acute liver side effect. The pharmaceutical companies normally apply animal studies and human trials to test the hepatotoxicity of a new drug during its developing period, and only the ones with low hepatotoxicity will be further investigated and allowed to be marketed. However there are still limitations on these hepatotoxicity-evaluating tests. First, hepatotoxicity are sometimes tested for interactions between the drug candidate and other approved drugs prior to marketing. However, a newly marketed drug might be taken by the patients with other drugs which are not included in the primary clinical trial drugs and may cause unpredictable side effects as a result. Furthermore, the number of the patients of the clinical trials is generally limited, such as in the range of dozens, hundreds, or thousands, since the acute severe liver cases occur at a rate of 0.1% or less, statistically there will be no acute liver poisoning case observed in the human trial with less than one thousand people, and only 10 acute cases in a clinical trial of 10,000 people. Even if these special cases (or other adverse effects with occurrence rate of less than 1%) were observed in the trial, they are generally excluded from the normal analysis and marked with “unknown causes” on the clinical reports, and will not stop the drug of being marketed. The largest pharmaceutical company in the world, Pfizer Inc., has recalled a new diabetic drug Rezulin recently. Prior to recall, the annual revenue of Rezulin was about 1 billion US dollars and was being taken by nearly 1 million diabetic patients worldwide. Food and Drug Administration recalled Rezulin after receiving several liver toxicity cases (a few dozens of patients were dead or needed liver transplants). In addition to the loss of the drug development cost and new drug revenue, a recall-induced litigation and legal liabilities could amount to hundreds of millions of dollars.
U.S. Pat. No. 5,730,138 disclosed a method which utilized a set of equipments to measure the blood pressure fluctuation of a patient's artery, then calculate frequencies of harmonic waves corresponding to the heart beat base frequency by Fourier Transform method. This United States patent also claims that the first harmonic wave obtained in the frequency analysis can indicate the blood circulating status and the function of the liver, and other harmonic waves (second, third harmonics, etc.) represent other organs of the body. However, the purpose of that case is mainly on the diagnosis of patients' blood circulating system, and that when determining whether the patient's liver function is normal, it needs to compare the characteristics of patients' liver harmonic wave with normal people to determine if the liver function is normal.
The prior art described above has not disclosed or suggested the prevention of acute liver side effects induced by drugs. For reducing the occurrence rate of acute liver side effects, the pharmaceutical companies often ask patients to have a blood test every month or every two months to examine the liver function, which includes measuring the concentrations of the liver enzymes (e.g., AST [also named SGOT], ALT [also named SGPT] and bilirubin) in the blood. When one of the three values is higher than the normal value and reaches a certain level (usually two to three fold higher than the normal value), the physician will instruct the patient to stop taking the drug. Since acute liver toxicity can occur within days or weeks, the monthly or bi-monthly test can only reduce the occurrence rate but cannot effectively prevent it from happening. Furthermore, the liver function test from blood samples not only is costly, but also causes pain (when drawing blood samples) and inconvenience (back and forth to the clinics) to the patients.
The inventor has found that a non-invasive pressure sensor and the equipment system containing the same can be used to detect the blood pressure pulse baseline of the patients before taking the drug, and the changes of the blood pressure pulse wave during the drug administration. The characteristics of the pulse changes can be detected in the clinical trial of the drug. The inventor has further found that regularly monitoring the changing value of the blood pressure wave characteristics during the drug taking period can detect some symptoms such as the liver poisoning or inflammation happening in the early period. Since the administrated drug will be degraded or transformed by the liver before being excreted, if the drug causes toxicity or damage to the liver cells and causes inflammation, the amount of blood flowing to the liver artery will be increased over the normal range to cope with the new oxygen demand and support the regeneration of the liver cells. Furthermore, swollen liver cells and their peripheral organs caused by the poisoning and inflammation will increase the resistance of the internal liver blood flow and hinder the blood flowing from the gastrointestinal vein through the portal vein into the liver, and result in portal hypertension and splanchnic venous bed pressure increase. Under these circumstances, to reduce the increased blood pressures, autonomic nervous system and regional tissue cells may release the vasodilating factors to expand blood vessels. Since the veins and arteries of the human body are centered in the heart and are into-connected to form a network, arterial pressure waveforms will be correspondingly changed by all the alterations on blood dynamic described above. Therefore, the measurement of arterial pressure waveforms and the monitoring of their altered amount can be the theoretical and technological basis for preventing acute liver side effects caused by drugs. The exact characteristics and the amount altered of the blood pressure waveforms (whether in the normal range caused by typical drug effects or abnormal caused by liver side effects) can be measured by analyzing the experimental results of human clinical trials. Accordingly, the abnormal liver functional symptom can be monitored, and an alarm and advice can be provided to the patient for stop taking the drug. The present invention is based on comparing the blood pressure waveform changes before and after the patients take the drug of the same persons, but not comparing a patient with other normal persons. In addition, the system apparatus of the present invention is easy to use at home, and the acquired data can be transmitted to the doctors via a variety of communication methods (e.g., telephone, internet, radio). The system apparatus of the present invention can reduce the medical costs and the pain and inconvenience of the patients.